Molecular Markers of Idiopathic Pulmonary Fibrosis Progression. 2. Specific Aims this application addresses the following NHLBI participation in Research and Research Infrastructure "Grand Opportunities" RC2 TOPIC: CTRIP: NHLBI Translational Research Implementation Program. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal, fibrotic disorder of the lung with an estimated prevalence of 30-80/100,000 in the United States but whose incidence is clearly rising (1). Over the last decade, improved histopathologic classification of the idiopathic interstitial pneumonias (of which IPF is one) has helped to distinguish disorders which are responsive to therapy from those which are associated with a poor prognosis and are relatively unresponsive to known therapies. The most common idiopathic interstitial pneumonia (IIP) is IPF, whose histopathologic pattern is usual interstitial pneumonia. IPF is associated with the worst prognosis of all IIPs with a median survival of 30-40 months from the time of diagnosis. Although numerous therapeutic clinical trials have been undertaken to slow the relentless progression of fibrosis in the lung, none has clearly identified a beneficial therapeutic regimen. The diagnosis of IPF can be confidently made when typical clinical symptoms, signs and radiographic findings are present. Making an accurate diagnosis is critical as an IPF diagnosis drives overall prognosis and is crucial to selecting the limited available therapies, including lung transplantation. An additional major challenge in the care of IPF patients is determining prognosis. The natural history of IPF is usually one of progressive decline in lung function that ultimately results in death from respiratory failure. However, longitudinal physiologic decline in IPF is quite heterogeneous and difficult to predict in individual patients. The practical implication of this variability in disease progression is highlighted by the discordant results of two recently reported pirfenidone trials. In both studies, the pirfenidone treated group exhibited a similar decrease in FVC percent predicted over follow-up (6.49%) while the placebo group decreased by 9.55% in one study and 7.23% in the other. This difference resulted in vastly different results from the primary analyses (p=0.001 in one and p=0.501 in the second). As many current treatment studies emphasize approximately one year outcomes, the ability to identify patients at risk for rapid disease progression would provide a key clinical advantage in the design inclusion and exclusion criteria for clinical trials and the interpretation of clinical responses to drug therapies in clinical practice. Disparate physiological approaches have been taken to identify disease progression, largely based on the ability to identify patients at risk of mortality, with varying results. Our group has refined the physiological approach to defining physiological disease progression by stratifying longitudinal change in FVC, DLCO or six minute walk performance as a function of baseline six-minute walk desaturation (13). An FVC decrease >10% or a DLCO decrease of at least 15% was shown to strongly predict subsequent mortality. Unfortunately, the incomplete relationship between physiological worsening and clinical events supports that disease progression is best defined using a composite approach including decreasing FVC and/or DLCO, acute exacerbations or mortality. This approach is now being utilized as the primary endpoint in a series of NIH (ACE Study) or industry sponsored therapeutic trials (ARTEMIS Study &BUILD 3). Identifying biologically relevant differences between IPF patients that remain stable versus those who progress is a crucial area of investigation. Several investigative groups, using incomplete or unvalidated methods to define intermediate disease progression, have suggested differences in gene expression of lung tissue or markers in blood or bronchoalveolar lavage. Our preliminary data indicate that TLR9, a hypomethylated CpG DNA receptor, is prominently expressed in surgical lung biopsies (SLB) from rapidly progressive IPF patients. Furthermore, IPF transbronchial biopsies (TBB)-derived fibroblasts exhibit similar migratory and proliferative properties compared with SLB-derived fibroblasts from the same patients. Additional preliminary data in peripheral blood monocyte mRNA whole genome expression arrays indicate a signature suggestive of rapid progression, Thus, it is clear that the next major advances in understanding the biology of IPF progression will come from studying biologic samples in highly characterized patients followed in a standard fashion. We hypothesize that biomarkers will reliably identify IPF patients who progress rapidly during the first 45 weeks of follow-up. We will address two Specific Aims: 1) Assemble a network of clinical centers to procure biologic samples from patients with recently diagnosed IPF and follow these patients for at least 45 weeks;2) Correlate and integrate biologically plausible biomarkers of disease activity obtained from multiple compartments (SLB, TBB, blood) from the same patient with longitudinal measures of disease progression. This comprehensive approach will allow an unprecedented understanding of the biological underpinnings of progressive IPF and allow its definition at a baseline visit. PUBLIC HEALTH RELEVANCE: Early diagnosis of Idiopathic Pulmonary Fibrosis (IPF) is key to providing the appropriate treatment for this incurable disease. This project will quickly enroll 135 clinical subjects from across the United States. The multiple specimens collected from this population will be used over a two year period by the nation's leading IPF basic science and clinical research teams to determine the early indicators of the ability to maintain stable health.